Mitigation of Microglia-mediated Acute Neuroinflammation and Tissue Damage by Heme Oxygenase 1 in a Rat Spinal Cord Injury Model.
Mitigation of Microglia-mediated Acute Neuroinflammation and Tissue Damage by Heme Oxygenase 1 in a Rat Spinal Cord Injury Model.
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血红素加氧酶 1 在大鼠脊髓损伤模型中减轻小胶质细胞介导的急性神经炎症和组织损伤。
DOI：
10.1016/j.neuroscience.2020.08.001
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发表时间：
2021
期刊：
影响因子：
3.3
通讯作者：
He Xu
中科院分区：
文献类型：
--
作者：
Lin Wenping;Chen Wenkai;Liu Kai;Ma Pengfei;Qiu Peng;Zheng Can;Zhang Xin;Tan Pingjuan;Xi Xiaojing;He Xu
急性神经炎症是脊髓损伤后继发性组织损伤的主要危险因素。抑制神经炎症将减少神经元死亡，有利于功能恢复。在目前的研究中，我们使用HO-1编码的慢病毒来刺激小胶质细胞，并将这些小胶质细胞过继转移到损伤的大鼠脊髓中。慢病毒诱导的外源性HO-1的过表达显著抑制SCI后小胶质细胞介导的炎症反应，如转移的小胶质细胞中促炎介质的较低表达所示。此外，总体SCI后神经炎症也被HO-1过表达的小胶质细胞抑制，如脊髓中较少的白细胞浸润和较低的促炎细胞因子产生所示。损伤脊髓组织损伤程度减轻，神经元凋亡减少，运动功能得到一定程度的改善。我们进一步证实了腺苷5′-单磷酸活化蛋白激酶（AMPK）信号通路参与了HO-1对小胶质细胞的调节作用，因为HO-1过表达增加了AMPKα的活化磷酸化。AMPK抑制剂化合物C可减弱HO-1对脂多糖刺激的小胶质细胞的抗炎作用。总之，我们证明了小胶质细胞HO-1减少急性SCI后神经炎症。我们的研究可能提供一个有前途的治疗方法，有利于脊髓损伤的恢复。
Acute neuroinflammation is the major detrimental factor that causes secondary tissue damage after spinal cord injury (SCI). Curbing neuroinflammation would reduce the neuronal death and benefit functional recovery. In the current study, we used a HO-1-encoding lentivirus to transduce microglia, and adoptively transferred these microglia into injured rat spinal cords. Lentivirus-induced overexpression of exogenous HO-1 significantly inhibited microglia-mediated inflammatory response after SCI, as demonstrated by lower expression of pro-inflammatory mediators in transferred microglia. In addition, the overall post-SCI neuroinflammation was also suppressed by HO-1-overexpressing microglia, as indicated by less leukocyte infiltration and lower pro-inflammatory cytokine production in the spinal cord. Consistently, the tissue damage and neuronal apoptosis were decreased in injured spinal cords, while the locomotor function was moderately improved. We further identified that adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling was involved in the regulatory effect of HO-1 on microglia, because HO-1 overexpression increased the activating phosphorylation of AMPKα. Moreover, the AMPK inhibitor compound C diminished the anti-inflammatory effect of HO-1 in lipopolysaccharide-stimulated microgliain vitro. Taken together, we proved that microglial HO-1 reduced acute post-SCI neuroinflammation. Our study might provide a promising therapeutic approach to benefit SCI recovery.